WO2025007776A1 - Composé fluorescent à base de nouveau vert d'indocyanine ir820, sa préparation et son application - Google Patents

Composé fluorescent à base de nouveau vert d'indocyanine ir820, sa préparation et son application Download PDF

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Publication number
WO2025007776A1
WO2025007776A1 PCT/CN2024/101326 CN2024101326W WO2025007776A1 WO 2025007776 A1 WO2025007776 A1 WO 2025007776A1 CN 2024101326 W CN2024101326 W CN 2024101326W WO 2025007776 A1 WO2025007776 A1 WO 2025007776A1
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Prior art keywords
indocyanine green
fluorescent
tumor
compound based
fluorescent compound
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Chinese (zh)
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黄楚森
宣集高
贾能勤
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Shanghai Fluoresoma Medical Technology Co Ltd
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Shanghai Fluoresoma Medical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent materials, e.g. electroluminescent or chemiluminescent
    • C09K11/06—Luminescent materials, e.g. electroluminescent or chemiluminescent containing organic luminescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1074—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms

Definitions

  • the present disclosure relates to the technical field of fluorescent compounds, and in particular to a fluorescent compound based on new indocyanine green IR820 and a preparation method and application thereof.
  • Fluorescence imaging has shown broad application prospects in basic biomedical research and clinical transformation such as precise intraoperative tumor resection.
  • One of the core technologies of fluorescence imaging is the creation of fluorescent probe molecules that can be used for imaging. Fluorescent probe molecules can dynamically track the occurrence and development of various physiological and pathological processes and diseases at the molecular level. Especially in the field of tumor visualization imaging, since fluorescent probe molecules can light up cancer cells in real time during surgery, they can help doctors more accurately determine tumor boundaries and find metastatic lesions.
  • fluorescent probe molecules can light up cancer cells in real time during surgery, they can help doctors more accurately determine tumor boundaries and find metastatic lesions.
  • the only fluorescent dyes approved by the FDA for clinical use are fluorescein, methylene blue, and indocyanine green (ICG).
  • fluorescein and methylene blue are limited to less than 700nm, they are easily interfered by the spontaneous background fluorescence signal of organisms when used for tumor fluorescence imaging.
  • their biological tissue penetration ability is also weak. Therefore, the fluorescent probes developed based on fluorescein and methylene blue are only suitable for use in open surgery and are easily interfered by the biological background fluorescence signal.
  • ICG is currently the only fluorescent dye approved by the FDA for fluorescent surgical navigation because its emission wavelength can reach about 800nm.
  • ICG dyes are easily photobleached after long-term excitation. Therefore, ICG is not light stable enough and cannot be excited for a long time in tumor fluorescence imaging, resulting in certain restrictions on its application.
  • ICG-derived dyes such as IRDye800CW and ZW800-1 dyes.
  • IRDye800CW dye introduces two sulfonic acid groups on the benzene ring
  • ZW800-1 dye introduces two positively charged quaternary ammonium salts on the side chain, it is quite different from the ICG structure in terms of charging mode (ICG carries two negative charges, which exist on the side chain).
  • IR820 is also known as the new indocyanine green. Compared with other fluorescent dyes based on ICG analogs such as IRDye800CW and ZW800-1, its structure completely retains the charging mode and parent nucleus structure of ICG in terms of charging mode and chemical structure.
  • IR820 dyes There are few tumor-targeted small molecule fluorescent probes based on IR820 dyes, and there are currently no organic small molecule fluorescent probes based on IR820 designed for integrins (especially integrin ⁇ v ⁇ 3) highly expressed on the surface of tumor cells.
  • the middle chlorine substitution of IR820 is the only group that can be used for coupling.
  • the middle chlorine group of IR820 is easily replaced by groups such as amino and thiol (Sci. China Chem.
  • the purpose of the present disclosure includes providing a fluorescent compound based on new indocyanine green IR820 and its preparation and application,
  • the present disclosure provides a fluorescent compound based on a new indocyanine green IR820, the molecular structure of which is shown in formula (1):
  • the present disclosure provides a method for preparing a fluorescent compound based on the novel indocyanine green IR820, wherein the compound represented by formula (2) is reacted with a precursor of a connecting arm and cRGD in sequence to obtain a target product;
  • R 1 is selected from halogen elements
  • the precursor of the connecting arm includes a compound having a structure shown in formula (3):
  • R2 includes a hydroxyl group
  • R3 includes a carboxyl group
  • n is 1-10.
  • R1 is Cl.
  • R2 is a hydroxyl group
  • R3 is a carboxyl group
  • n 2.
  • the molar ratio of the compound represented by formula (2), the precursor of the linker arm, and cRGD is 1:(1-10):(1-3), and can be specifically 1:1:1, or 1:10:3, or 1:5:2, or any intermediate value within this range.
  • the compound represented by formula (2) is sequentially reacted with the precursor of the linker arm in an organic solvent system (eg DMF), sodium hydride is also added to the reaction system, the reaction temperature is room temperature, and the reaction time is 3-5 hours.
  • organic solvent system eg DMF
  • the intermediate product obtained by the reaction of the compound represented by formula (2) with the precursor of the linker arm is firstly activated by EDC and NHS in NMP or DMF solvent, and then reacted with cRGD at room temperature.
  • the present disclosure provides an application of a fluorescent compound based on new indocyanine green IR820 in the preparation of a surgical fluorescent navigation probe.
  • the present disclosure provides a fluorescent composition, which includes the fluorescent compound based on the new indocyanine green IR820 as described above, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a fluorescence imaging system, comprising a fluorescence detection device and a fluorescent probe, wherein the fluorescent probe comprises the fluorescent compound based on the new indocyanine green IR820 as described above.
  • the present disclosure also provides a fluorescence imaging method for non-diagnostic purposes, which includes: administering a fluorescent probe to a subject, and then performing fluorescence imaging on the subject; wherein the subject includes living cells, active physiological tissues of animals or living animals; and the fluorescent probe includes the fluorescent compound.
  • the present disclosure provides an application of the fluorescent compound based on the new indocyanine green IR820 in specific binding to integrin.
  • the present disclosure provides an application of the fluorescent compound based on the novel indocyanine green IR820 in targeting integrins highly expressed on the surface of tumor cells.
  • the present disclosure provides an application of the fluorescent compound based on the novel indocyanine green IR820 in targeting integrin ⁇ v ⁇ 3 highly expressed on the surface of tumor cells.
  • the present disclosure provides a use of the fluorescent compound based on the new indocyanine green IR820 in fluorescence angiography of tumor sites.
  • the tumor includes a tumor with high expression of integrin.
  • the tumor includes a tumor with high expression of integrin ⁇ v ⁇ 3.
  • the tumor includes but is not limited to breast cancer tumor and/or brain glioma.
  • the beneficial effects of the present invention include:
  • the fluorescent probe disclosed in the present invention is based on the ICG core structure and has better tumor targeting and photostability than the FDA-approved ICG.
  • the fluorescent probe disclosed in the present invention completely retains the charge mode and parent core structure of ICG in terms of charge mode and chemical structure. Therefore, in terms of biocompatibility, it is closest to ICG, which has been approved by the FDA and has been clinically verified to have good biocompatibility for a long time.
  • the IR820-cRGD provided in the present invention is an organic small molecule fluorescent probe. Compared with the IR820-based nanoprobes and IR820-conjugated antigen or antibody probes (antibody-IR820 conjugates) disclosed in the prior art, IR820-cRGD has the advantages of an organic small molecule probe, that is, IR820-cRGD can efficiently penetrate the cell membrane and enter the cell, thereby achieving more efficient imaging of the tumor site.
  • the present disclosure introduces a linker with a phenolic hydroxyl group into the chlorine in IR820, and then further couples with the desired targeting group using the linker.
  • the chlorine on IR820 is first replaced by the phenolic hydroxyl group to form a stable phenol-substituted IR820, which avoids the situation that the chlorine atom on IR820 is easily affected by coupling auxiliary reagents such as amino or thiol groups when IR820 is directly coupled with the targeting group, resulting in unsuccessful coupling synthesis. Therefore, the present disclosure provides a synthetic method for successfully coupling IR820 with a targeting group.
  • FIG. 1 is a mass spectrum of IR820-COOH in an embodiment of the present disclosure
  • FIG. 2 is a mass spectrum of IR820-cRGD in an embodiment of the present disclosure.
  • FIG. 3 is a HPLC chart of IR820-cRGD in an embodiment of the present disclosure.
  • FIG. 4 is a fluorescence and bright field photograph of IR820-cRGD and different cells in an embodiment of the present disclosure.
  • FIG. 5 is an in vivo fluorescence imaging diagram of IR820-cRGD in a mouse tumor according to an embodiment of the present disclosure.
  • FIG. 6 is a graph showing the change in fluorescence signal of IR820-cRGD at different concentrations in a mouse tumor site over time in an embodiment of the present disclosure.
  • FIG. 7 is a 6-hour fluorescence imaging diagram of IR820-cRGD in an orthotopic breast cancer site in mice according to an embodiment of the present disclosure.
  • cRGD was purchased from Xi’an Qiyue Biotechnology Co., Ltd.
  • a fluorescent compound provided in this embodiment can be named IR820-cRGD, and its synthesis route is as follows:
  • the synthesis method of the fluorescent compound includes the following steps:
  • the instrument model used for cell imaging was Leica TCS SP5II confocal laser scanning microscope using a HC ⁇ PLAPO 63 ⁇ oil objective (NA:1.40).
  • the experiment was conducted in three groups, one in normal CHO cells, one in breast cancer MCF-7 cells, and one in cervical cancer Hela cells.
  • the cultured cell culture medium was first aspirated, washed with PBS buffer, and then washed with DMEM or 1640.
  • 10 ⁇ L of the prepared probe concentration 1mM DMSO mother solution was measured and added to a 2ml culture dish containing fresh DMEM or 1640 culture medium.
  • the excess culture medium was first removed, and then the excess probe was washed with PBS buffer (pH7.4), and then the imaging test was performed using a confocal fluorescence microscope.
  • Figure 4 shows the fluorescence imaging of the probe in three cell types. It can be shown that the probe has a large selective fluorescence signal for tumor cells. It shows the potential of the probe for tumor imaging.
  • IR820-cRGD Three tumor-bearing mice were injected with 10 ⁇ M IR820-cRGD pure water solution, DMSO pure water solution with equivalent probe concentration, and IR820 pure water solution through the tail vein. After 2 hours, the imaging of the mouse tumor site was observed by a small animal in vivo imaging instrument. As shown in Figure 5, IR820-cRGD showed a very bright fluorescence signal at the mouse tumor site. On the contrary, the pure water solution had no fluorescence signal, and the non-targeted IR820 had only a weak fluorescence signal. The results show that the targeted probe IR820-cRGD greatly improves the imaging effect of IR820 dye for living tumors.
  • Example 2 Compared with Example 1, most of the steps are the same, except that the molar ratio of IR820, p-hydroxyphenylpropionic acid, and cRGD is adjusted to 1:1:1.
  • Example 2 Compared with Example 1, most of the steps are the same, except that the molar ratio of IR820, p-hydroxyphenylpropionic acid, and cRGD is adjusted to 1:10:3.
  • Example 3 Compared with Example 3, the tumor was induced by MDA-MB-231-LD in situ breast cancer. Pure saline, IR820 and three concentrations of IR820-cRGD saline solutions were injected respectively through the tail vein. The fluorescence signal at different times of the mouse tumor site was observed by a small animal in vivo imaging instrument. The results show that the targeted probe IR820-cRGD greatly improves the imaging effect of IR820 dye for in situ breast cancer. It was found that the optimal imaging time was 6 hours and the most suitable concentration was 10nmol (as shown in Figure 6). As shown in Figure 7, the imaging effect of 6 hours is intuitively shown.
  • IR820-cRGD shows a very bright fluorescence signal at the in situ breast cancer site of mice.
  • pure saline has no fluorescence signal, and there is only a weak fluorescence signal of IR820 without targeting.
  • the fluorescent compound based on the new indocyanine green IR820 provided in the present invention has good tumor targeting and photostability, has near-infrared fluorescence emission, good tumor targeting, biocompatibility, low cytotoxicity, and strong biological tissue penetration. It can be applied to targeted fluorescence imaging of tumor cells and living tumors, and has great promotion and application value.

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Abstract

La présente divulgation se rapporte au domaine technique des composés fluorescents. En particulier, l'invention concerne un composé fluorescent à base de nouveau vert d'indocyanine IR820, et une préparation et une application de celui-ci. La structure moléculaire du composé fluorescent est telle que représentée dans la formule (1). Par rapport à la technologie existante, la sonde fluorescente de la présente invention présente une émission de fluorescence proche infrarouge, un ciblage de tumeur et une biocompatibilité satisfaisants, une faible cytotoxicité et une forte pénétration de tissu biologique. Il peut être appliqué à l'imagerie par fluorescence ciblée de cellules tumorales et de tumeurs vivantes, et il est prévu d'être en outre appliqué à la navigation chirurgicale par fluorescence.
PCT/CN2024/101326 2023-07-05 2024-06-25 Composé fluorescent à base de nouveau vert d'indocyanine ir820, sa préparation et son application Ceased WO2025007776A1 (fr)

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US19/382,210 US20260061080A1 (en) 2023-07-05 2025-11-06 Fluorescent compound based on new indocyanine green ir820, and preparation and use thereof

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CN202310818545.2A CN116947829B (zh) 2023-07-05 2023-07-05 一种基于新吲哚菁绿ir820的荧光化合物及其制备和应用
CN202310818545.2 2023-07-05

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CN116947829B (zh) * 2023-07-05 2025-09-23 上海内瑟汐医疗科技有限公司 一种基于新吲哚菁绿ir820的荧光化合物及其制备和应用

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CN105130876A (zh) * 2015-09-08 2015-12-09 湖南博瑞新特药有限公司 新吲哚菁绿的制备工艺
CN109020955A (zh) * 2018-08-02 2018-12-18 深圳大学 一种分子探针、制备方法及其应用
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